Hydroxy containing FXR (NR1H4) modulating compounds

A compound according to the following Formula (1), an enantiomer, diastereomer, tautomer, solvate, prodrug or pharmaceutical acceptable salt thereof

• wherein:
• R is selected from the group consisting of hydrogen, halogen, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, halo-C1-6-alkyl, C0-6-alkylene-R7, C0-6-alkylene-O—R7, C0-6-alkylene-CN, C0-6-alkylene-NR7R8, O—C3-10-cycloalkyl, O—C1-6-alkylene-O—R7, O—C3-10-heterocycloalkyl, C0-6-alkylene-CO2R7, C0-6-alkylene-C(O)R7, C0-6-alkylene-C(O)NR7R8, C0-6-alkylene-C(O)NR7SO2R7, C0-6-alkylene-N(R7)C(O)R7, C0-6-alkylene-SOx—R7, C0-6-alkylene-SO3H, C0-6-alkylene-SO2—NR7R8, C0-6-alkylene-SO2—NR8COR7, C0-6-alkylene-N(R7)SO2—R8, and C0-6-alkylene-SO2—C3-10-heterocycloalkyl,
• wherein alkylene, cycloalkyl, heterocycloalkyl and the 5- or 6-membered heteroaryl are unsubstituted or substituted by 1 to 4 substituents independently selected from the group consisting of halogen, CN, C1-3-alkyl, halo-C1-3-alkyl, OH, oxo, CO2H, SO3H, O—C1-3-alkyl and O-halo-C1-3-alkyl;
• R7 is independently selected from the group consisting of hydrogen, C1-6-alkyl, halo-C1-6-alkyl, C0-6-alkylene-C3-8-cycloalkyl, C0-6-alkylene-C3-8-heterocycloalkyl, 5- or 6-membered heteroaryl and phenyl, wherein alkyl, alkylene, cyclolalkyl, heterocycloalkyl, phenyl and heteroaryl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of halogen, CN, OH, oxo, CO2H, C1-3-alkyl, halo-C1-3-alkyl, O—C1-3-alkyl, O-halo-C1-3-alkyl, SO3H and SO2—C1-3-alkyl;
• R8 is independently selected from the group consisting of hydrogen, C1-6-alkyl, halo-C1-6-alkyl and C3-6-cycloalkyl;
• or R7 and R8 when taken together with the nitrogen to which they are attached may complete a 3- to 8-membered ring containing carbon atoms and optionally containing 1 or 2 heteroatoms selected from O, S or N, wherein the ring is unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of fluoro, OH, oxo, C1-4-alkyl and halo-C1-4-alkyl;
• A is a 6-10 membered mono- or bicyclic aryl or a 5-10 membered mono- or bicyclic heteroaryl containing 1 to 5 heteroatoms independently selected from the group consisting of N, O and S, wherein aryl and heteroaryl are unsubstituted or substituted with one or two groups independently selected from the group consisting of OH, halogen, CN, O—C1-6-alkyl, O-halo-C1-6-alkyl, C1-6-alkyl, halo-C1-6-alkyl, C3-6-cycloalkyl, C6-6-heterocycloalkyl and halo-C3-6-cycloalkyl;
• Q is a C3-10-cycloalkyl ring, or C6-10-bridged cycloalkyl ring wherein the —O—CH2—Z-substituent is not directly adjacent to substituent A, wherein when Q is a bi- or multicyclic ring system, a carbon atom may optionally be replaced by a oxygen, SOx or NR7;
• Z is selected from
• wherein
• L is selected from the group consisting of a bond, C1-3-alkylene and C1-3-alkylene-O—;
• Y is selected from the group consisting of phenyl, pyridyl, pyridyl-N-oxide, pyrimidyl, pyridinonyl, pyrimidinonyl, C4-8-cycloalkyl and C4-8-heterocycloalkyl, wherein phenyl, pyridyl, pyridyl-N-oxide, pyrimidyl, pyridinonyl, pyrimidinonyl, C4-8-cycloalkyl and C4-8-heterocycloalkyl are substituted with R2 and R3 and optionally substituted one or two times with a group selected from fluoro, chloro, CN, NH2, NH(C1-3-alkyl), N(C1-3-alkyl)2, C1-3-alkyl, fluoro-C1-3-alkyl, OH, C1-3-alkoxy, fluoro-C1-3-alkoxy, C3-6-cycloalkyl and fluoro-C3-6-cycloalkyl;
• R1 is selected from the group consisting of C1-4-alkyl and C3-6-cycloalkyl, wherein C1-4-alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, hydroxy, C1-3-alkoxy and fluoro-C1-3-alkoxy, and C3-6-cycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, hydroxy, C1-3-alkyl, fluoro-C1-3-alkyl, C1-3-alkoxy and fluoro-C1-3-alkoxy;
• R2 and R3 are independently selected from the group consisting of hydrogen, halogen, C1-3-alkyl, halo-C1-3-alkyl, C1-3-alkoxy, halo-C1-3-alkoxy, cyclopropyl and fluoro-cyclopropyl;
• R4 is independently selected from the group consisting of halogen, C1-3-alkyl, halo-C1-3-alkyl, C1-3-alkoxy, halo-C1-3-alkoxy, C3-6-cycloalkyl, C1-3-alkylene-O—C1-3-alkyl and fluoro-C3-6-cycloalkyl;
• R5 is selected from the group consisting of hydrogen, fluoro, CH3, CHF2 and CF3;
• n is selected from 0, 1, 2, 3 and 4;
• x is independently selected from 0, 1 and 2.